4-70523877-T-C

Position:

• chr4-70523877-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_212557.4(AMTN):​c.148T>C​(p.Ser50Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00614 in 1,613,634 control chromosomes in the GnomAD database, including 310 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.022 (120 hom., cov: 32)
  • Exomes 𝑓: 0.0044 (190 hom.)
• Consequence: AMTN NM_212557.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.25

Genes affected

AMTN (HGNC:33188): (amelotin) The mineralized portions of teeth, the dentin and enamel, are formed by mesenchyme-derived odontoblasts and epithelium-derived ameloblasts, respectively. As ameloblasts differentiate, they deposit specific proteins necessary for enamel formation, including amelogenin (AMELX; MIM 300391), enamelin (ENAM; MIM 606585), and ameloblastin (AMBN; MIM 601259), in the organic enamel matrix. Amelotin is specifically expressed in maturation-stage ameloblasts (Iwasaki et al., 2005 [PubMed 16304441]).[supplied by OMIM, Mar 2008]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0030688941).
• BP6: Variant 4-70523877-T-C is Benign according to our data. Variant chr4-70523877-T-C is described in ClinVar as [Benign]. Clinvar id is 3042027.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.07 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AMTN	NM_212557.4	c.148T>C	p.Ser50Pro	missense_variant	4/9	ENST00000339336.9
AMTN	NM_001286731.2	c.145T>C	p.Ser49Pro	missense_variant	4/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AMTN	ENST00000339336.9	c.148T>C	p.Ser50Pro	missense_variant	4/9	1	NM_212557.4	P4
AMTN	ENST00000504451.1	c.145T>C	p.Ser49Pro	missense_variant	4/9	1		A2

Frequencies

GnomAD3 genomes AF: 0.0224 AC: 3411 AN: 152158 Hom.: 119 Cov.: 32

Gnomad AFR AF: 0.0722

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0106

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.0410

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.0191

GnomAD3 exomes AF: 0.0102 AC: 2570 AN: 251024 Hom.: 69 AF XY: 0.0103 AC XY: 1404 AN XY: 135668

Gnomad AFR exome AF: 0.0719

Gnomad AMR exome AF: 0.00449

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000381

Gnomad SAS exome AF: 0.0385

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000291

Gnomad OTH exome AF: 0.00474

GnomAD4 exome AF: 0.00444 AC: 6491 AN: 1461358 Hom.: 190 Cov.: 30 AF XY: 0.00523 AC XY: 3802 AN XY: 726958

Gnomad4 AFR exome AF: 0.0732

Gnomad4 AMR exome AF: 0.00476

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0369

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000158

Gnomad4 OTH exome AF: 0.00714

GnomAD4 genome AF: 0.0224 AC: 3415 AN: 152276 Hom.: 120 Cov.: 32 AF XY: 0.0224 AC XY: 1666 AN XY: 74458

Gnomad4 AFR AF: 0.0721

Gnomad4 AMR AF: 0.0106

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000579

Gnomad4 SAS AF: 0.0408

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.0189

Alfa AF: 0.00436 Hom.: 35

Bravo AF: 0.0246

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0769 AC: 339

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.0118 AC: 1436

Asia WGS AF: 0.0210 AC: 73 AN: 3476

EpiCase AF: 0.000383

EpiControl AF: 0.000476

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

AMTN-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 03, 2020

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.015	T;.
Eigen	Benign	-0.080
Eigen_PC	Benign	0.038
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.57	T;T
MetaRNN	Benign	0.0031	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	L;.
MutationTaster	Benign	0.68	N;N
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-3.5	D;D
REVEL	Benign	0.064
Sift	Uncertain	0.027	D;D
Sift4G	Benign	0.22	T;T
Polyphen		0.36	B;B
Vest4		0.20
MPC		0.45
ClinPred		0.029	T
GERP RS		3.9
Varity_R		0.62
gMVP		0.48

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs34803339; hg19: chr4-71389594;